BY MICHAEL C. PURDY
MORE THAN A CENTURY AGO, Alois Alzheimer, a German psychiatrist, first identified the neurodegenerative brain condition that came to be known as Alzheimer’s disease.
Finding ways to diagnose and treat this devastating disease has frustrated scientists and clinicians ever since.
Now the long and hard-fought campaign against Alzheimer’s has reached a potentially significant milestone: the launch of the first clinical trials to test whether new drug treatments given before dementia can prevent the disease.
The trial is being conducted by the Dominantly Inherited Alzheimer’s Network Trial Unit (DIAN-TU), led by principal investigator Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine.
Randall Bateman, MD, talks with DIAN-TU participant Natalie Shriver about the trial.
PHOTO BY ROBERT BOSTON
Prevention, the research suggests, has a better chance of succeeding than treatment after cognitive impairment.
Steps on the journey
School of Medicine researchers have made many key contributions along the journey to the new DIAN-TU trial.
The late Leonard Berg, MD, the founding director of the university’s Knight Alzheimer’s Disease Research Center, and current director John C. Morris, MD, were among the first to assert and prove that Alzheimer’s harms patients’ brains for many years prior to dementia onset and memory loss.
Washington University scientists have led the quest for new treatments and for biological markers that can identify people who seem normal but whose brains are actively being damaged by presymptomatic Alzheimer’s disease.
Researchers have characterized disease markers in cerebrospinal fluid and have tested neuroimaging techniques for detecting Alzheimer’s, making it possible to diagnose the disease much earlier.
A long, slow descent
Rare, inherited forms of Alzheimer’s are particularly devastating — striking much earlier in life than sporadic forms of the disease — with symptoms becoming apparent in some mutation carriers in their 30s or 40s. Children who inherit one of the mutations typically show signs of Alzheimer’s at about the same age as their parents.
To expand researchers’ opportunities to work with these families, Morris founded the Dominantly Inherited Alzheimer’s Network (DIAN) in 2008. This global network generated a pool of qualified volunteers and forged a research partnership determined to understand forms of Alzheimer’s caused by genetic mutations.
With the help of DIAN family members, researchers created a detailed timeline of the brain’s long, slow descent into Alzheimer’s dementia, showing, for example, that brain plaques can be detected 15 years prior to symptoms. These plaques are made mostly of amyloid beta. This protein, which abnormally accumulates in the brain of people with Alzheimer’s, is thought to play a role in brain cell damage and death.
~20-30 YEARS PRIOR
Cerebrospinal fluid analysis reveals abnormal levels of precursor proteins, an early warning sign
~15 YEARS PRIOR
Neurofibrillary tangles (gray) have already gnarled some tissue; amyloid beta protein (yellow) deposits in clumps
~10 YEARS PRIOR
Protein deposits increase, with negative effects on cognitive functions
~5 YEARS PRIOR
Tissue begins to atrophy and shrink; some clinical measures can detect a functional decline
Difficulties due to memory and cognitive loss; impaired function in job and social activities
3-7 YEARS UNTIL DEATH
Marked decline as the person becomes increasingly demented, culminating in disability and finally death
Before damage is done
Two drugs targeting the protein amyloid beta (Aβ) could stop it from damaging the brain before any symptoms occur.
As visualized below, an antibody called solanezumab (s) removes soluble molecules of Aβ (yellow). Another antibody, gantenerumab (g), binds to and removes larger aggregates of Aβ.
Starting the new trial
With the support of these findings and other groundwork from the DIAN study, Bateman established the DIAN Trials Unit. Now, DIAN participants and others who have an inherited Alzheimer’s mutation are undergoing the first trials of preclinical treatments that target amyloid beta. Many of these participants do not have any symptoms, but researchers know these patients will get Alzheimer’s disease and approximately when they will get it.
“Trying to prevent Alzheimer’s symptoms from occurring is a new strategy, but much of what we’ve learned in recent years about Alzheimer’s and the brain has suggested that prevention has a significantly better chance of succeeding than treatment after cognitive impairment,” said Morris, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology.
The trial is testing two drug treatments designed to eliminate amyloid beta from the brain at different points in the plaque production process. Researchers plan to test additional treatments with different mechanisms of action in this and future trials. The treatments were nominated by the DIAN Pharma Consortium, composed of 11 pharmaceutical companies that have been advising researchers on the planning of the trial. From those nominations, the Alzheimer’s researchers chose the trial drugs.
“We believe that the diverse portfolio of drugs and approaches of the DIAN-TU trial will accelerate the discovery of an effective treatment for Alzheimer’s,” Bateman said. “This trial is possible because of the outstanding support of multiple stakeholders, including patients and family members, pharmaceutical partners, the Alzheimer’s Association, the National Institutes of Health, academic researchers and highly dedicated trial operations groups.”
The trial is funded by a unique mix of private and public resources, including: major grants from the National Institutes of Health (NIH) and the Alzheimer’s Association; treatment donations and funding from the drugs’ manufacturers Roche and Eli Lilly & Co.; donation of a new agent for imaging brain plaques, Amyvid, by Avid Radiopharmaceuticals Inc., a wholly owned subsidiary of Lilly; and donation by CogState of computerized cognitive skills tests to help assess function in participants.
Patients undergo brain scans before and after taking the drug to track if the drug is doing what it was designed to do in the DIAN-TU trial.
PHOTO BY ROBERT BOSTON
This initial study involves 210 participants. Three of every four will receive active forms of trial drugs; the fourth will receive a placebo. Researchers will track biological markers of Alzheimer’s in participants’ cerebrospinal fluid and on brain scans, looking for any indicators that the disease process is slowing or stopping.
If successful, scientists plan to move directly into Phase III clinical trials to prove that Alzheimer’s can be slowed or stopped. The hope is that knowledge gained in the trials can be applied to the more common late-onset Alzheimer’s.
Brent Whitney, 34, of Grove, Okla., is asymptomatic, but has an inherited form of Alzheimer’s and is a DIAN participant. The lives of his grandmother and 10 of her 13 siblings were cut short by the Alzheimer’s gene mutation, and the mutation continues to affect succeeding generations of the family.
“The start of this trial is a very exciting moment in Alzheimer’s disease research, and it gives me renewed hope for a future without Alzheimer’s,” Whitney said. “I hope my grandchildren someday learn of this condition in history books, like I learned about polio.”